European Journal of Medical Genetics xxx (2014) 1e5
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Genotypeephenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion Isabella Fanizza a, Sara Bertuzzo b, Silvana Beri c, Elisabetta Scalera a, Angelo Massagli a, Maria Enrica Sali d, Roberto Giorda c, Maria Clara Bonaglia b, * a
Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Ostuni, Brindisi, Italy Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, Lecco, Italy Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy d Child Psychopathology Unit e Neuropsychology of Developmental Disorders, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 November 2013 Accepted 15 April 2014 Available online xxx
Microdeletion 12p13.33, though very rare, is an emerging condition associated with variable phenotype including a specific speech delay sound disorder, labelled childhood apraxia of speech (CAS), intellectual disability (ID) and neurobehavioral problems. Here we report a de novo 2.3 Mb interstitial 12p13.33-p13.32 deletion in a 5 year-old child with mild ID, speech delay, microcephaly, muscular hypotonia, and joint laxity. In contrast to previously reported patients with 12p13.33 monosomy, our patient’s interstitial deletion spans the 12p13.33-12p13.32 region with the distal breakpoint within intron 12 of CACNA1C. Phenotypeegenotype comparison between our case, previously reported patients, and subjects with 12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability of the patients’ phenotype, since the gene resulted disrupted or entirely deleted in the majority of reported patients. In addition, phenotypic features such as microcephaly, muscular hypotonia, and joint laxity are mainly present in patients with monosomy of 12p13.33 extending to the 12p13.32 portion. A common region of w300 kb, harbouring EFCAB4B and PARP11, is deleted in patients with microcephaly while a second region of w700 kb, including TSPAN9 and PMTR8, could be associated with muscle hypotonia and joint laxity. These data reinforce the hypothesis that multiple haploinsufficient genes and age-dependent observation may concur to generate the variable phenotype associated with 12p13.33 deletion. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: 12p13.33 Deletion CACNA1C Speech delay Array-CGH Interstitial deletion Microcephaly
1. Introduction Deletions involving the distal portion of 12p are among the least frequent subtelomeric rearrangements detected in a selected group of more than 11,000 patients with developmental disabilities [Ravnan et al., 2006]. The rarity of this rearrangement has been later confirmed following the advent of microarray-based technology. To date, microdeletions detected by genome-wide array analysis at 12p13.33, either de novo [Rooryck et al., 2009; Thevenon et al., 2013; Vargas et al., 2012] or inherited [Abdelmoity et al., 2011; Thevenon et al., 2013], have been reported in 12 index patients [Abdelmoity et al., 2011; Baker et al., 2002; MacDonald et al., 2010; Madrigal et al., 2012; Thevenon et al., 2013; Vargas et al.,
* Corresponding author. Tel.: þ39 031 877 913; fax: þ39 031 877 499. E-mail address: [email protected] (M.C. Bonaglia).
2012]. The phenotype, though variable, is mainly characterized by speech delay with or without [Thevenon et al., 2013] intellectual disability (ID) of variable degree and behavioural abnormalities. The recent findings of de novo and inherited interstitial deletions of 2.76 Mb and 1.39 Mb [Abdelmoity et al., 2011; Thevenon et al., 2013], respectively, led to the identification of a new 12p13.33 locus, including ELKS/ERC1, whose deletion is associated with the speech disorder childhood apraxia of speech (CAS), also labelled developmental verbal dyspraxia (DVD) [Thevenon et al., 2013]. Here we report on a child with de novo 2.3 Mb interstitial 12p13.33-p13.32 microdeletion, whose main phenotype is characterized by mild ID and speech delay. Comparative phenotypic evaluation of subjects with small deletions partially overlapping the 12p13.33 locus allows us to propose that haploinsufficiency of CACNA1C (MIM 114205) and other genes may influence the phenotypic variability of patients with monosomy of the 12p13.33 subtelomeric region.
http://dx.doi.org/10.1016/j.ejmg.2014.04.009 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Fanizza I, et al., Genotypeephenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.009
2
I. Fanizza et al. / European Journal of Medical Genetics xxx (2014) 1e5
2. Clinical report Informed consent was obtained from both parents of the patient. The five-year-old boy came to our attention for intellectual disabilities and speech delay. He was born at 39 weeks of gestation, after caesarean section, to non-consanguineous 26year-old mother and 29-year-old father with unremarkable family history. Birth weight was 2160 g (3rd percentile). His younger brother, now aged 15 months, has normal psychomotor development. At birth, he manifested severe breathing and feeding problems and was transferred to the intensive care unit for ten days. Bartter syndrome was suspected. Early motor milestones were in range: he sat at between 6 and 9 months, walked at 15 months, thought uncoordinatedly. Language and learning difficulties were noticed early. First words were pronounced at 2 1/2 years. At the age of 5 years (last evaluation), he had mild ID. The IQ was calculated by WPPSI-III (Wechsler Preschool and Primary Scale of IntelligenceeThird Edition) with this result: full scale IQ 52; verbal IQ 53 (standard score: information 4, vocabulary 2, word reasoning 1); performance IQ 62 (standard score: block design 3, matrix reasoning 4, picture concepts 6); processing Speed 52 (standard score: symbol search 3, coding 1); general language 53 (receptive vocabulary 1, picture naming 3). A digit cancellation test (Nepsy-II “Visual Attention”) showed difficulties in distractor inhibition and selective and sustained attention, with long inspection time and slow motor performance. Forward and backward digit span scores were 2.4 SD and 1.9 SD respectively. Visuo-Spatial Memory (Test BVS e Corsi) was 3.0 SD. The patient had fine motor disorder: Nepsy-II scales “Imitating Hand Positions” 1 Scaled Scores (SS), “Manual Motor Sequences” 1 SS. The VABS showed global motor problems: motor skills AE was 2 years 4 months. The oro-facial dyspraxia was exhibited using the Nepsy-II scale “Oromotor Sequences” 1 SS. Linguistic assessment with a comprehensive battery (Nepsy-II) showed problems in “Comprehension of Instructions” 1 SS, “Speeded Naming” < 2 Percentile, “Phonological Processing” 1 SS, “Repetition of Nonsense Words” 1 SS, “Verbal Fluency” 2 SS. These difficulties had an important influence on mnemonic abilities (Nepsy-II) “Narrative Memory” 4 SS, “Sentence Repetition” 3 SS (Table 1). The Vineland Adaptive Behaviour Scale (VABS) was administered to both parents. His global age equivalent (AE) was less than 2 years 2 months; receptive language and expressive skills score was 2 years 9 months; socialization AE was less than 1 year 11 months; daily living skills AE was 2 years 4 months; motor skills AE was 2 years 4 months. His score on the “Child Global Assessment of Functioning Scale” (CGAS) was 40, corresponding to “Major impairment to functioning in several areas”. No behavioural abnormalities were noticed. His height was 104 cm (10e25th centile), weight 15 kg (3e10th centile) and OFC 46 cm (3 SD). He showed subtle facial dysmorphisms, including brachycephaly, low hairline, synophrys, long eyelashes, thin lips, ears with short and convoluted anti-helices and V-shaped notches, arched palate (Fig. 1A). He presented diffuse muscular hypotonia, joint laxity, and global clumsiness. Flat-footedness bilaterally with enlarged base and walking on tips were noticed. Brain MRI showed no abnormalities, except for a slight supratentorial asymmetry (right greater than left); EEG showed slow fronto-parietal abnormalities in sleep starting bilaterally on a poorly modulated basic framework. Conventional cytogenetic studies showed a normal karyotype (46,XY); fragile-X molecular tests were normal.
Table 1 Cognitive assessment of the patient. Test reference: NEPSY-II (“A Developmental NEuroPSYchological Assessment”) Italian Edition C. Urgesi, F. Fabbro, 2011; BVSCorsi (“Batteria per la valutazione visiva e spaziale”) I.C. Mammarella, C. Cornoldi; BVN 5-11 (Batteria di Valutazione Neuropsicologica per l’età evolutiva) P. S. Bisiacchi, M. Cendron, M. Gugliotta, Tressoldi e Vio, 2005 Ed. Erickson. Cognitive function
Test
Score
Executive functions Attention Short term memory Working memory Visuo-spatial memory
Visual attention (Nepsy-II) Forward digit span (BVN 5e11) Backward digit span (BVN 5e11) Test di Corsi (BVS-Corsi)
5 SS 2.4 SD 1.9 SD 3.0 SD
Comprehension of instructions (Nepsy-II) Speeded naming (Nepsy-II) Phonological processing (Nepsy-II) Verbal fluency (Nepsy-II) Repetition of nonsense words (Nepsy-II) Oromotor sequences (Nepsy-II)
1 SS
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Genotypeephenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion Isabella Fanizza a, Sara Bertuzzo b, Silvana Beri c, Elisabetta Scalera a, Angelo Massagli a, Maria Enrica Sali d, Roberto Giorda c, Maria Clara Bonaglia b, * a
Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Ostuni, Brindisi, Italy Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, Lecco, Italy Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy d Child Psychopathology Unit e Neuropsychology of Developmental Disorders, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 November 2013 Accepted 15 April 2014 Available online xxx
Microdeletion 12p13.33, though very rare, is an emerging condition associated with variable phenotype including a specific speech delay sound disorder, labelled childhood apraxia of speech (CAS), intellectual disability (ID) and neurobehavioral problems. Here we report a de novo 2.3 Mb interstitial 12p13.33-p13.32 deletion in a 5 year-old child with mild ID, speech delay, microcephaly, muscular hypotonia, and joint laxity. In contrast to previously reported patients with 12p13.33 monosomy, our patient’s interstitial deletion spans the 12p13.33-12p13.32 region with the distal breakpoint within intron 12 of CACNA1C. Phenotypeegenotype comparison between our case, previously reported patients, and subjects with 12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability of the patients’ phenotype, since the gene resulted disrupted or entirely deleted in the majority of reported patients. In addition, phenotypic features such as microcephaly, muscular hypotonia, and joint laxity are mainly present in patients with monosomy of 12p13.33 extending to the 12p13.32 portion. A common region of w300 kb, harbouring EFCAB4B and PARP11, is deleted in patients with microcephaly while a second region of w700 kb, including TSPAN9 and PMTR8, could be associated with muscle hypotonia and joint laxity. These data reinforce the hypothesis that multiple haploinsufficient genes and age-dependent observation may concur to generate the variable phenotype associated with 12p13.33 deletion. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: 12p13.33 Deletion CACNA1C Speech delay Array-CGH Interstitial deletion Microcephaly
1. Introduction Deletions involving the distal portion of 12p are among the least frequent subtelomeric rearrangements detected in a selected group of more than 11,000 patients with developmental disabilities [Ravnan et al., 2006]. The rarity of this rearrangement has been later confirmed following the advent of microarray-based technology. To date, microdeletions detected by genome-wide array analysis at 12p13.33, either de novo [Rooryck et al., 2009; Thevenon et al., 2013; Vargas et al., 2012] or inherited [Abdelmoity et al., 2011; Thevenon et al., 2013], have been reported in 12 index patients [Abdelmoity et al., 2011; Baker et al., 2002; MacDonald et al., 2010; Madrigal et al., 2012; Thevenon et al., 2013; Vargas et al.,
* Corresponding author. Tel.: þ39 031 877 913; fax: þ39 031 877 499. E-mail address: [email protected] (M.C. Bonaglia).
2012]. The phenotype, though variable, is mainly characterized by speech delay with or without [Thevenon et al., 2013] intellectual disability (ID) of variable degree and behavioural abnormalities. The recent findings of de novo and inherited interstitial deletions of 2.76 Mb and 1.39 Mb [Abdelmoity et al., 2011; Thevenon et al., 2013], respectively, led to the identification of a new 12p13.33 locus, including ELKS/ERC1, whose deletion is associated with the speech disorder childhood apraxia of speech (CAS), also labelled developmental verbal dyspraxia (DVD) [Thevenon et al., 2013]. Here we report on a child with de novo 2.3 Mb interstitial 12p13.33-p13.32 microdeletion, whose main phenotype is characterized by mild ID and speech delay. Comparative phenotypic evaluation of subjects with small deletions partially overlapping the 12p13.33 locus allows us to propose that haploinsufficiency of CACNA1C (MIM 114205) and other genes may influence the phenotypic variability of patients with monosomy of the 12p13.33 subtelomeric region.
http://dx.doi.org/10.1016/j.ejmg.2014.04.009 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Fanizza I, et al., Genotypeephenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.009
2
I. Fanizza et al. / European Journal of Medical Genetics xxx (2014) 1e5
2. Clinical report Informed consent was obtained from both parents of the patient. The five-year-old boy came to our attention for intellectual disabilities and speech delay. He was born at 39 weeks of gestation, after caesarean section, to non-consanguineous 26year-old mother and 29-year-old father with unremarkable family history. Birth weight was 2160 g (3rd percentile). His younger brother, now aged 15 months, has normal psychomotor development. At birth, he manifested severe breathing and feeding problems and was transferred to the intensive care unit for ten days. Bartter syndrome was suspected. Early motor milestones were in range: he sat at between 6 and 9 months, walked at 15 months, thought uncoordinatedly. Language and learning difficulties were noticed early. First words were pronounced at 2 1/2 years. At the age of 5 years (last evaluation), he had mild ID. The IQ was calculated by WPPSI-III (Wechsler Preschool and Primary Scale of IntelligenceeThird Edition) with this result: full scale IQ 52; verbal IQ 53 (standard score: information 4, vocabulary 2, word reasoning 1); performance IQ 62 (standard score: block design 3, matrix reasoning 4, picture concepts 6); processing Speed 52 (standard score: symbol search 3, coding 1); general language 53 (receptive vocabulary 1, picture naming 3). A digit cancellation test (Nepsy-II “Visual Attention”) showed difficulties in distractor inhibition and selective and sustained attention, with long inspection time and slow motor performance. Forward and backward digit span scores were 2.4 SD and 1.9 SD respectively. Visuo-Spatial Memory (Test BVS e Corsi) was 3.0 SD. The patient had fine motor disorder: Nepsy-II scales “Imitating Hand Positions” 1 Scaled Scores (SS), “Manual Motor Sequences” 1 SS. The VABS showed global motor problems: motor skills AE was 2 years 4 months. The oro-facial dyspraxia was exhibited using the Nepsy-II scale “Oromotor Sequences” 1 SS. Linguistic assessment with a comprehensive battery (Nepsy-II) showed problems in “Comprehension of Instructions” 1 SS, “Speeded Naming” < 2 Percentile, “Phonological Processing” 1 SS, “Repetition of Nonsense Words” 1 SS, “Verbal Fluency” 2 SS. These difficulties had an important influence on mnemonic abilities (Nepsy-II) “Narrative Memory” 4 SS, “Sentence Repetition” 3 SS (Table 1). The Vineland Adaptive Behaviour Scale (VABS) was administered to both parents. His global age equivalent (AE) was less than 2 years 2 months; receptive language and expressive skills score was 2 years 9 months; socialization AE was less than 1 year 11 months; daily living skills AE was 2 years 4 months; motor skills AE was 2 years 4 months. His score on the “Child Global Assessment of Functioning Scale” (CGAS) was 40, corresponding to “Major impairment to functioning in several areas”. No behavioural abnormalities were noticed. His height was 104 cm (10e25th centile), weight 15 kg (3e10th centile) and OFC 46 cm (3 SD). He showed subtle facial dysmorphisms, including brachycephaly, low hairline, synophrys, long eyelashes, thin lips, ears with short and convoluted anti-helices and V-shaped notches, arched palate (Fig. 1A). He presented diffuse muscular hypotonia, joint laxity, and global clumsiness. Flat-footedness bilaterally with enlarged base and walking on tips were noticed. Brain MRI showed no abnormalities, except for a slight supratentorial asymmetry (right greater than left); EEG showed slow fronto-parietal abnormalities in sleep starting bilaterally on a poorly modulated basic framework. Conventional cytogenetic studies showed a normal karyotype (46,XY); fragile-X molecular tests were normal.
Table 1 Cognitive assessment of the patient. Test reference: NEPSY-II (“A Developmental NEuroPSYchological Assessment”) Italian Edition C. Urgesi, F. Fabbro, 2011; BVSCorsi (“Batteria per la valutazione visiva e spaziale”) I.C. Mammarella, C. Cornoldi; BVN 5-11 (Batteria di Valutazione Neuropsicologica per l’età evolutiva) P. S. Bisiacchi, M. Cendron, M. Gugliotta, Tressoldi e Vio, 2005 Ed. Erickson. Cognitive function
Test
Score
Executive functions Attention Short term memory Working memory Visuo-spatial memory
Visual attention (Nepsy-II) Forward digit span (BVN 5e11) Backward digit span (BVN 5e11) Test di Corsi (BVS-Corsi)
5 SS 2.4 SD 1.9 SD 3.0 SD
Comprehension of instructions (Nepsy-II) Speeded naming (Nepsy-II) Phonological processing (Nepsy-II) Verbal fluency (Nepsy-II) Repetition of nonsense words (Nepsy-II) Oromotor sequences (Nepsy-II)
1 SS
